Potential new causes for the odor-producing disorder trimethylaminura

February 14, 2017

Just before Rare Disease Day 2017, a study from the Monell Center and collaborating institutions provides new insight into the causes of trimethylaminura (TMAU), a genetically-transmitted metabolic disorder that leads to accumulation of a chemical that smells like rotting fish.

Although TMAU has been attributed solely to mutations in a single gene called FMO3, the new study combined sensory and genetic approaches to identify additional genes that may contribute to TMAU. The findings indicate that genetic testing to identify mutations in the FMO3 gene may not be sufficient to identify the underlying cause of all cases of TMAU.

TMAU is classified as a "," meaning that it affects less than 200,000 people in the United States. However, its actual incidence remains uncertain, due in part to inconclusive diagnostic techniques.

"Our findings may bring some reassurance to people who report fish-like odor symptoms but do not have mutations in the FMO3 gene," said Monell behavioral geneticist Danielle R. Reed, PhD, a senior author on the study.

The socially and psychologically distressing symptoms of TMAU result from the buildup of trimethylamine (TMA), a chemical compound produced naturally from many foods rich in the dietary constituent, choline. Such foods include eggs, certain legumes, wheat germ, saltwater fish and organ meats. TMA, which has a foul, fishy odor, normally is metabolized by the liver enzyme flavin-containing monooxygenase 3 (FMO3) into an odorless metabolite.

People with TMAU are unable to metabolize TMA, presumably due to defects in the underlying FMO3 gene that result in faulty instructions for making functional FMO3 enzymes. The TMA, along with its associated unpleasant odor, then accumulates and is excreted from the body in urine, sweat, saliva, and breath.

However, some people who report having the fish odor symptoms of TMAU do not have severely disruptive mutations in the FMO3 gene. This led the researchers to suspect that other genes may also contribute to the disorder.

In the new study, reported in the open access journal BMC Medical Genetics, the research team combined a gene sequencing technique known as exome analysis with sophisticated computer modeling to probe for additional TMAU-related genes.

The study compared sensory, metabolic and genetic data from ten individuals randomly selected from 130 subjects previously evaluated for TMAU at the Monell Center.

Each subject's body odor was evaluated in the laboratory by a trained sensory panel before and after a metabolic test to measure production of TMA over 24 hours following ingestion of a set amount of choline.

Although the choline challenge test confirmed a diagnosis of TMAU by revealing a high level of urinary TMA in all 10 subjects, genetic analyses revealed that the FMO3 gene appeared to be normal in four of the 10. Additional analyses revealed defects in several other genes that could contribute to the inability to metabolize the odorous TMA.

"We now know that genes other than FMO3 may contribute to TMAU. These new genes may help us better understand the underlying biology of the disorder and perhaps even identify treatments," said Reed.

TMAU's odor symptoms may occur in irregular and seemingly unpredictable intervals. This makes the disease difficult to diagnose, as patients can appear to be odor-free when they consult a health professional.

This was evidenced in the current study. Although all of the subjects reported frequent fish-odor symptoms, none was judged by the sensory panel to have a fish-like odor at the time of the choline challenge.

Monell analytical organic chemist George Preti, PhD, also a senior author, commented on the diagnostic implications of the combined findings, "Regardless of either the current sensory presentation TMAU or the FMO3 genetics, the choline challenge test will confirm the accumulation of TMA that reveals the presence of the disorder."

Moving forward, the researchers would like to repeat the genetic analyses in a larger cohort of TMAU patients without FMO3 mutations to confirm which other genes are involved in the disorder.

"Such information may identify additional odorants produced by TMAU-positive patients, and inform the future development of gene-based therapies" said Preti.

Explore further: Undiagnosed trimethylaminuria may explain many cases of personal malodor

More information: Yiran Guo et al, Genetic analysis of impaired trimethylamine metabolism using whole exome sequencing, BMC Medical Genetics (2017). DOI: 10.1186/s12881-017-0369-8

Related Stories

Undiagnosed trimethylaminuria may explain many cases of personal malodor

August 31, 2011
Scientists from the Monell Center report that approximately one third of patients with unexplained body malodor production test positive for the metabolic disorder trimethylaminuria (TMAU). A definitive diagnosis offers relief ...

Recommendations made for genetic testing for Trimethylaminuria

January 20, 2012
(Medical Xpress) -- Recommendations for genetic testing of an inherited disorder known as trimethylaminuria or ‘fish odor syndrome’ have been produced by researchers including Professor Ian Phillips from Queen Mary, ...

Odor biomarker for Alzheimer's disease

January 14, 2016
A new study from the Monell Center, the U.S. Department of Agriculture (USDA), and collaborating institutions reports a uniquely identifiable odor signature from mouse models of Alzheimer's disease. The odor signature appears ...

Earwax: A new frontier of human odor information

February 12, 2014
Scientists from the Monell Center have used analytical organic chemistry to identify the presence of odor-producing chemical compounds in human earwax. Further, they found that the amounts of these compounds differ between ...

Elderly humans can be identified by their unique body odor: research

May 30, 2012
New findings from the Monell Center reveal that humans can identify the age of other humans based on differences in body odor. Much of this ability is based on the capacity to identify odors of elderly individuals, and contrary ...

Recommended for you

Association found between abnormal cerebral connectivity and variability in the PPARG gene in developing preterm infants

December 12, 2017
(Medical Xpress)—A team of researchers with King's College London and the National Institute for Health Research Biomedical Research Centre, both in the U.K., has found what they describe as a strong association between ...

Large genetic study links tendency to undervalue future rewards with ADHD, obesity

December 11, 2017
Researchers at University of California San Diego School of Medicine have found a genetic signature for delay discounting—the tendency to undervalue future rewards—that overlaps with attention-deficit/hyperactivity disorder ...

Gene variants identified that may influence sexual orientation in men and boys

December 8, 2017
(Medical Xpress)—A large team of researchers from several institutions in the U.S. and one each from Australia and the U.K. has found two gene variants that appear to be more prevalent in gay men than straight men, adding ...

Disease caused by reduction of most abundant cellular protein identified

December 8, 2017
An international team of scientists and doctors has identified a new disease that results in low levels of a common protein found inside our cells.

Study finds genetic mutation causes 'vicious cycle' in most common form of amyotrophic lateral sclerosis

December 8, 2017
University of Michigan-led research brings scientists one step closer to understanding the development of neurodegenerative disorders such as ALS.

Mutations in neurons accumulate as we age: The process may explain normal cognitive decline and neurodegeneration

December 7, 2017
Scientists have wondered whether somatic (non-inherited) mutations play a role in aging and brain degeneration, but until recently there was no good technology to test this idea. A study published online today in Science, ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.